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Gauvin et al., Pharmaceut Reg Affairs 2018, 7:1

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Pharmaceutical Regulatory Affairs: Open Access
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armaceutic
DOI: 10.4172/2167-7689.1000202

Op
en Access
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ISSN: 2167-7689

Research Article Open Access

Marijuana Toxicity: Heavy Metal Exposure Through State-Sponsored Access


to “la Fee Verte”
David V Gauvin*, Zachary J Zimmermann, Joshua Yoder and Rachel Tapp
Department of Neurobehavioral Sciences, MPI Research, 54943 North Main Street, Mattawan, MI 49071, USA

Abstract
Federally unregulated, Marijuana Growth Organizations (MGOs) have now provided a path to exposures to the
neurotoxicity of heavy metals. The lack of US Food and Drug Administration (FDA) and US Environmental Protection
Agency (EPA) testing and oversight of the MGOs now threatens the public health. Agribusiness and botany experts
proclaim the value of cannabis as a perfect rotating plant for phytoremediation programs to help scavenge heavy
metals from soils prior to seeding the land for food product. Cannabis has a high affinity for soil contaminants without
affecting its own heartiness. However, “legal” marijuana plots have burgeoned in the “Emerald Triangle” of Northern
California, Oregon and Washington. According to the FDA’s toxicology program, the largest sources of heavy metals
(HMs) are the environments surrounding abandoned or active mines. The history of gold, platinum, coal, and copper
mining in these grow areas now threatens the end-user; the plants ability to “scrub the earth” of these highly toxic
HMs provides main stream smoke contamination to the consumer. Published reports of cannabis users showing
hearing loss and neurological changes to temporal lobe structures involved in audition as well as learning and memory.
The apoptotic cascade of cytotoxic events initiated by heavy metals is linked to the progression of Alzheimer’s and
Parkinson’s disease, as well as hearing loss related to brain stem and temporal lobe neurotoxicity.

Keywords: Intracerebroventricular; Intraventricular; FDA; Cannabis; 2) Quality control by chemical test (s) (e.g., analytical tests such as
Drug administration; Central nervous system; Regulatory; Neurotoxicity spectroscopic and/or chromatographic methods that capture the active
or chemical constituents of a botanical drug substance).
Introduction
3) Manufacturing (agricultural) control (e.g., process validation).
One of the first international collaborative efforts in drug control
focused on restricted access to absinthe – also known as the “green 4) Biological assay (e.g., a biological assay that reflects the drug’s
fairy” (la fée verte). Absinthe is an alcohol distillate from wormwood known or intended mechanism of action) and clinical data (for details
that contains thujone. Thujone, a major component of the absinthe regarding use of clinical data in ensuring therapeutic consistency.
drink is neurotoxic, although the current view rather downgrades its There are statutory thresholds for the formal adoption of any
risk to humans [1]. However, thujone is still restricted by the US FDA new molecular entity to be accepted as medicine in the US. In 2018
(21 CFR §172.510, dated April 1, 2017). Marijuana represents the new marijuana is not medicine, it remains in Schedule I of the Controlled
green fairy sponsored for its medical utility. Substances Act as a hallucinogen with no approved medical use in the
US.
Experimental
There are five criteria that define “medical use”, all of which must
Cannabis be satisfied:
The medical panacea Marijuana is a Schedule I controlled substance (1) the drug’s chemistry must be known and reproducible,
under international treaty commitments [2] and codified (as federal
law) by the U.S. Congress into the Comprehensive Drug Abuse and (2) there must be adequate safety studies,
Control Act of 1973 ([3] also known as the Controlled Substances (3) there must be adequate and well-controlled studies proving
Act [CSA]). In spite of the popular press, medicine is not defined efficacy,
by public vote, community councils, or state legislatures. Under the
Food, Drug and Cosmetic Act, the only legally-competent authority (4) the drug must be accepted by qualified experts, and
to determine whether any substance is a “medicine” is the executive (5) the scientific evidence must be widely available. In 2017 the
branch cabinet post position of the Department of Health and Human National Academies of Science published an update on their previous
Services (DHHS), and through a Memo of Understanding (MOU), position on therapeutic cannabis. In the most recent review of the
the Commissioner of the Food and Drug Administration. Only after literature the NAS team concluded that “there is substantial evidence
a thorough review of both nonclinical and clinical data it is the FDA
alone, that fulfils the legislative mandate to determine what is and what
isn’t medicine in this country. Because of the heterogeneous nature of
a botanical drug and possible uncertainty about its active constituents, *Corresponding author: David V Gauvin, Director, Department of Neurobehavioral
one of the critical issues that the FDA is mandated by legal statutes to Sciences, MPI Research, 54943 North Main Street, Mattawan, MI 49071, USA, Tel:
address is the assurance that the therapeutic effect for each marketed +1269-668-3336; E-mail: david.gauvin@mpiresearch.com
drug product batches are consistent. Each formulation on the market is Received March 11, 2018; Accepted March 22, 2018; Published April 01, 2018
required to meet strict control standards. Citation: Gauvin DV, Zimmermann ZJ, Yoder J, Tapp R (2018) Marijuana Toxicity:
Heavy Metal Exposure Through State-Sponsored Access to “la Fee Verte”. Pharmaceut
In general, the FDA ensures therapeutic consistency by a “totality Reg Affairs 7: 202. doi: 10.4172/2167-7689.1000202
of the evidence” approach, including the following considerations:
Copyright: © 2018 Gauvin DV, et al. This is an open-access article distributed under
1) Botanical raw material control (e.g., agricultural practice and the terms of the Creative Commons Attribution License, which permits unrestricted
collection). use, distribution, and reproduction in any medium, provided the original author and
source are credited.

Pharmaceut Reg Affairs, an open access journal Volume 7 • Issue 1 • 1000202


ISSN: 2167-7689
Citation: Gauvin DV, Zimmermann ZJ, Yoder J, Tapp R (2018) Marijuana Toxicity: Heavy Metal Exposure Through State-Sponsored Access to “la
Fee Verte”. Pharmaceut Reg Affairs 7: 202. doi: 10.4172/2167-7689.1000202

Page 2 of 10

that cannabis is an effective treatment for chronic pain in adults”, Many proponents of “medical marijuana” base their objections
however in their review the committee summarized their findings as: to drug control status based solely on Item #3. While the statutory
control of marijuana is based, in part, on the lack of accepted safety
The majority of studies on pain cited in Whiting et al. (2015)
(no danger), proponents often make the false claim that marijuana is
evaluated nabiximols outside the United States. In their review, the
not “dangerous” and is “safer” than alcohol (non-controlled substance)
committee found that only a handful of studies have evaluated the use
and is not attributed to many documented cause-of-deaths (i.e. LD50’s
of cannabis in the United States, and all of them evaluated cannabis in
in animals). The marijuana proponents seem to restrict their definition
flower form provided by the National Institute on Drug Abuse that was
either vaporized or smoked. In contrast, many of the cannabis products of “dangerous” to “lethality” or “deaths”. Under the law, the term
that are sold in state-regulated markets bear little resemblance to the “danger” is generally defined through property law statutes and is
products that are available for research at the federal level in the United different than the common connotation of the American vernacular.
States (p. 89). Water is not inherently dangerous, but spilled water on the floor of
department store meets the litmus test for public danger. Clothes
Thus, while the use of cannabis for the treatment of pain is supported detergent packets are not inherently dangerous; allowing access to
by well-controlled clinical trials as reviewed above, very little is known the packet for easy consumption by children meets the litmus test of
about the efficacy, dose, routes of administration, or side effects of “dangerous situation” that may further jeopardize the adults’ parental
commonly used and commercially available cannabis products in the rights.
United States. Given the ubiquitous availability of cannabis products in
much of the nation, more research is needed on the various forms, routes A dangerous instrument is any substance which, under the
of administration, and combination of cannabinoids (p. 90) circumstances in which it is used, attempted to be used, or threatened
to be used, is highly capable of creating a substantial risk of injury when
The National Academies of Science [4] has chosen their words it is used in a reasonably foreseeable manner. Generally, a dangerous
poorly. While their review acknowledges that their conclusion was substance is a risk that children or young adults cannot appreciate or
based on a majority of studies conducted outside of the U.S. using the avoid due to their immaturity or ignorance (is not known) or appreciated
cannabinoid combination product, Nabiximols (Sativex™), an extract of by the adults of legal age. For example, heroin (3,6-diacetylmorphine)
cannabis containing tetrahydrocannabinol and cannabidiol, approved is a Schedule I drug in the US, but it is a pharmacologically potent
as a botanical drug in the United Kingdom in 2010, their conclusion analgesic opioid (therapeutic use) in other countries. However, heroin
was not a tacit approval of cannabis (the plant material), per se. The does not have acceptable medical use in the US, based solely on the
gelatin encapsulated product, THC in sesame-seed oil (Marinol™), is lack of the full appreciation for the pharmacology of the drug, its
already approved in the US. Sativex™ and Marinol™ are not cannabis
rate of entry into the CNS, its dependence producing potential, its
(as legally defined), they are constituent elements of the plant.
actual illicit abuse patterns, as well as its abuse liability characteristics.
Analogously, morphine and codeine, are natural alkaloids of opium,
Pharmaceutical-grade heroin lacks the adulterants of street/illicit
but opium is not an approved medicine under international or national
supplies and is pharmaceutically pure; it still has no medical use in the
statutes. This is important to note because when Dr. Donald Abrams
US. There is limited knowledge of these pharmacological attributes in
[5], one of the review board members of the NAS team, published his
the general population, and certainly limited appreciation for the full
recent 2018 notice of result summaries of the NAS review, he modified
impact of these critical factors when or if the drug was taken outside
the conclusion to state “the report concluded that there was conclusive
the scope of medical supervision. Therefore, heroin is a dangerous drug
or substantial evidence that Cannabis or cannabinoids are effective
for the treatment of pain in adults”. The disjunctive statement of the and has Schedule I control status.
Abrams report is not identical to the Academies’ conclusion statement. In contrast to the stability and purity of pharmaceutical
Sativex™ and Marinol™ are not cannabis – they are constituent elements manufactured heroin, marijuana is an unstable weed, it is an
of the marijuana plant, much like thebaine, morphine and codeine in entourage substance. Marijuana contains over 650 other chemical
the opium poppy (papaver somniferum). This use of mixed metaphors substances beside Tetrahydrocannabinol (THC). The concentrations
in the cannabis debate is common and is used to confuse the message. and presence of these chemicals vary between growth cycles
As of this date (2018) there is insufficient valid, reliable and legally- and, more importantly, vary between plants from the same stock
defensible scientific data to support a conclusion of therapeutic use of source. The concentrations of THC and the approximate 64 other
marijuana plant under the Food, Drug and Cosmetic Act (FDandCA) cannabinoids in the plant is not controlled by genetics. There is
in the United States. In spite of the popular press, there remains a an almost universal belief that unlike tobacco, marijuana smoke
paucity of credible well-controlled randomized clinical trial data to is benign [6,7]. The threat to human health is based, in part, on
demonstrate that marijuana meets the legitimate, statutory and legally- the generally held naïve belief of its safety, its long history of actual
defensible criteria as an analgesic, anticonvulsant, antispasmodic, abuse, and the total lack of awareness or control of the phytotoxicity
antianxiety, or any other effective intervention in any disease process of other chemicals contained within the plant materials.
that would meet the standard “litmus test” for new drug application Proof of drug-induced toxicity does not have to be established by
licensure in the U.S. It is, however, a naturally occurring intoxicant. demonstrating that marijuana administration is directly cytotoxic or
There is a three-pronged definition of substances placed in Schedule “causes cancer”. The neuronal insult may be activated by inhalation of
I control status: marijuana smoke that produces injury via a second or tertiary pathway.
There is precedent set to show that normal brain circuitry can produce a
1) the drug or substance has a high potential for abuse; “built in” pattern of selective vulnerability that is likely to be important
2) the drug or other substance has no currently accepted medical determinants of cell death (e.g. excitotoxic injuries, glutamate surge,
use in treatment in the United States; etc.). With respect to this review, the danger of marijuana consumption
includes the presence of Heavy Metals (HM) and their duplicitous roles
3) there is a lack of accepted safety for use of the drug or other in cytotoxicity.
substance under medical supervision.

Pharmaceut Reg Affairs, an open access journal Volume 7 • Issue 1 • 1000202


ISSN: 2167-7689
Citation: Gauvin DV, Zimmermann ZJ, Yoder J, Tapp R (2018) Marijuana Toxicity: Heavy Metal Exposure Through State-Sponsored Access to “la
Fee Verte”. Pharmaceut Reg Affairs 7: 202. doi: 10.4172/2167-7689.1000202

Page 3 of 10

State-sponsored marijuana initiatives have spawned an agricultural Kaplan [13] California grown patient-advocate or “medical” marijuana
boon in the number of legal and illegal Marijuana Growth Organizations was submitted by the end users requesting analysis for contaminants.
(MGOs) that have been given unfettered access to grow, harvest and Thirty-three percent of all submitted samples were found to be
distribute a variety of cannabis plant materials with no knowledge contaminated with pesticides. The most commonly found pesticide in
of quality, integrity, or quantitative composition of what is being the California samples was paclobutrazol, a plant growth regulator. This
administered to human consumers. In the delusion of “compassionate is of great concern because this pesticide is not registered by the U.S.
care” many physicians’ have been duped into a false sense of security Environmental Protection Agency (EPA) for use on food crops. Sullivan
with home-grown cultivars and MGO supplied “medicines” that are et al., [14] have previously reported that up to 70% of paclobutrazol is
consumed without any federal regulatory control or oversight. Of great transferred into the smoke stream. Two other pesticides found in the
interest to drug regulators and environmental safety toxicologists is the US samples were bifenthrin (a pyrathroid insecticide) and myclobutanil
report that medical marijuana supplies have been independently tested (a systemic fungicide). In 2015, myclobutanil was found in Colorado-
and found to contain rodenticide, herbicides, and pesticide residues. grown marijuana by the Colorado Department of Agriculture (http://
The link between environmental contaminants and marijuana toxicity www.coloradogreenlab.com/blog/eagle-20-and-myclobutanil-in-
is certainly not new. Forty years ago, Alpers [8] admonished that: the-context-of-cannabis-cultivation-and-consumption). Aside from
environmental chemical contamination the medical use of marijuana
Intentional or unintentional exposure to environmental chemicals
has been linked to other health threats associated with poor quality
could enhance or inhibit the activity of hepatic mixed function
control standards during growth or harvest, such as aspergillosis [15-
oxidases that metabolise drugs and other foreign chemicals, as well as
17]. With a physician’s signature on a prescription, state-approved
endogenous substrates such as steroid hormones. A major source of
medical marijuana may now be the new “la fée verte”, the green fairy
such exposure may be occupational. Exposure to the heavy metal, lead,
supplying toxic agrochemical residues or plant fungal contamination
has been shown to inhibit drug metabolism; whereas intensive exposure
to dying and sick patients under the ruse of “compassionate care” – but
to chlorinated insecticides, and other halogenated hydrocarbons
the situation is more dire than this.
such as polychlorinated biphenyls, has been shown to enhance the
metabolism of test drugs such as antipyrine and phenylbutazone. Cannabis: The “Blessing” Can Be a Scurge
In late 2017, an independent journalist, Lester Black reported that Botanists have been touting the efficiency and benefits of certain
big recreational marijuana producers have swallowed up most of the plants and trees to the ecosystems by their ability to transfer elements
green market, pushing out the small-scale growers of the black and from abiotic into biotic environments [18]. There are plants that
medical markets. From January through September of 2017, Black accumulate excessive metals. The use of plants for environmental
[9] reported that the 10 largest farms in Washington harvested 16.79 restoration is an emerging technology and the plants capable
of all the dry weight weed grown in the state, which is more than the of accumulating higher levels of metals have been grown in the
share produced by the 500 smallest farms combined (13.12%). The contaminated soils [19]. Large agribusinesses are interested in plant
consolidation of cannabis farming will inevitability become a large- rotations that help to sustain development of healthy soils and that can
scale agribusiness that will start to drive down production costs. decontaminate metal polluted air, soil, and water [20]. On one hand
According to Black [9], current regulations restrict growth plot size in the metal extraction ability of plants is of great concern regarding a
the western states. Washington has expanded the maximum farm size possible entrance into food chain but on the other hand, this ability
from 30,000 square feet to 90,000. California plans on capping farms at of plants can be used as an alternative technology to remediate
1 acre, or 43,560 square feet, when the market first launches, however, contaminated soils. Phytoextraction can be defined as the use of living
there is no limit to the number of licenses each state registrant is allowed plants to absorb and accumulate metals from the soil into the aerial
to own. With agribusinesses now involved the large-scale production parts, which are harvested with conventional agricultural methods [21].
and harvesting techniques now come into effect. Fertilizers, pesticides, By scheduled field rotations the phytoextraction capabilities of non-
insecticides, fungicides, miticides, and growth stimulators appear to be food plants can “clean up” contaminated soils prior to planting of the
the norm – ganja growth is now “large farma” and there is no federal food crops [22]. Phytoextraction then is a cost effective, environmental
oversight. Cannabis is not a hybrid plant, it is an unstable weed. friendly technology used for cleaning of polluted soils to the advantage
Agricultural/industrial contaminants of cultivated marijuana of food development. Cannabis has been found to be an exceptional
should be a significant source of concern to the health status of phytoextractor.
marijuana users [10]. In 2016, Nathan Russo [11] reported 22 out All elements of the biosphere are adulterated by a variety of inorganic
of 26 marijuana samples were positive when analyzed for pesticide and organic pollutants as a result of man-made environmental activities
contamination in cultivation plots from the State of Washington such as mining. A variety of biological resources have been investigated
(USA). Many harbored multiple contaminants attaining levels 10’s and employed in attempts to clean up the metal polluted sites. These
of thousands of Parts Per Billion (ppb) and exceeding the upper limit technologies have gained considerable momentum under-developed
of quantitation. These included 45 distinct agents from every class of nations and are currently in the process of commercialization in the
insecticides, miticides, fungicides, synergists and growth regulators, industrialized nations, as well [23-25]. Plant and plant-rotations
including organophosphates and organochlorides. Cuypers et al. [12] designed to remove industrial/environmental pollutants from the
reported finding pesticides in 64.3% of 72 cannabis plant samples from environment are targeting the toxic effects of HM on the health of all
indoor growth plots and in 65.2% of 46 carbon filter cloth samples living organisms, this is known as phytoremediation. Phyto-extraction
taken from the air supply of the fruticetum. Overall, 19 pesticides of heavy metals from contaminated soils has the advantage of being a
belonging to different chemical classes were identified in marijuana more economic in situ alternative to other forms of clean up and, more
harvested for human consumption, including o-phenylphenol, importantly, is a great advertising ploy for garnering public opinion
bifenazate, cypermethrin, imidacloprid, propamocarb, propiconazole and support to the agribusiness. The soil based heavy metals of interest
and tebuconazole, which are consistent with the commonly reported to toxicologists are, at a minimum, iron (Fe), zinc (Zn), chromium
pesticides in the literature. In a 2015 report by Raber, Elzinga and (Cr), lead (Pb), nickel (Ni), cadmium (Cd) and arsenic (As).

Pharmaceut Reg Affairs, an open access journal Volume 7 • Issue 1 • 1000202


ISSN: 2167-7689
Citation: Gauvin DV, Zimmermann ZJ, Yoder J, Tapp R (2018) Marijuana Toxicity: Heavy Metal Exposure Through State-Sponsored Access to “la
Fee Verte”. Pharmaceut Reg Affairs 7: 202. doi: 10.4172/2167-7689.1000202

Page 4 of 10

Phytoextraction targets ecotoxicologically the most relevant soil The mining industry, past and present, in Californian, Oregon,
fraction of these metals, i.e. the bioavailable fraction. HM extraction Washington and Colorado are expansive. The automobile emission
and accumulation by plants depends upon the species and the efficiency residues are consistent with the astronomical traffic patterns of the
of absorption [26,27]. For example, plants on cadmium contaminated western states. These two man-made sources are the leading cause of
soil can absorb and accumulate cadmium due to its high mobility in environmental HM pollution products in soil and water. HMs have
the soil-plant system allowing its easy entrance into the food chain been deposited by sludge water run-off, excavated earth materials
and causes toxic effects in animals [28,29]. A large number of factors dumped as mine depth increased, and by the presence of US military
control metal accumulation and bioavailability associated with soil bases and nuclear test facilities that capriciously deposited radioactive
and climatic conditions, plant genotype and agronomic management, (cobalt, uranium, strontium, cesium, etc.) and inert HMs from
including: active/passive transfer processes, sequestration and weapon testing and training (lead, chromium, nickel, etc.) in the same
speciation, redox states, the type of plant root system and the response geographical areas as mines and automobiles [47].
of plants to elements in relation to seasonal cycles [30].
The crop productivity of the agribusiness in 3rd world countries
In order to achieve rapid growth and high yield extensive fertilizers has been advanced by the use of marijuana (industrial hemp) to hyper-
are applied to plants; fertilizers not only provide nutrients to plants accumulate industrial waste products to convert wastelands into
but can also change the speciation and mobility of metals in soil [21]. cultivated land, especially the area contaminated with heavy metal
Nitrogen, phosphorus and potassium are the most essential chemical pollution (lead, copper, zinc, cobalt, and cadmium) [48,49].
fertilizers for growth of plants under both in vivo and in vitro conditions
[31]. Ed Rosenthal [32], referred to as the “best-known marijuana Marijuana is a hyper-accumulator for cobalt. Cobalt and
horticulturists in America” (p. xiii), describes the demand for critical compounds that release cobalt ions in vivo, which would now include
nutrients in the fertilizers will vary with the growing conditions and marijuana, have been recently listed as carcinogenic by the American
changes during the plant’s life cycle. Marijuana uses more nitrogen Association for Cancer Research [50]. As a constituent element of
during the vegetative stage (prior to flowering) when compared to marijuana grown in contaminated soils of northern California, Oregon
later stages and uses more phosphorous as the flower begins followed and Washington, cobalt represents one of the hidden toxic dangers to
by increased demand for potassium after fertilization to aid flower the state-sponsored medicine programs. In the California medicinal
formation and seed production ([32], page 157). HM uptake into cannabis distribution system quality control is not mandated and
vegetables and grain increases with application of chemical fertilizers dispensary systems are more likely to submit the highest quality
[33-36]. Agribusiness use of large plot production of recreational or product for any required analysis. Therefore, advertised stock qualities
medical marijuana sets the stage for a public health crisis based on its from state-sponsored dispensaries are influenced by sample submission
“natural” chemical cleaning properties of soil HMs. bias and the reported data might not reflect the entire product range of
toxic substances contained in the state-sponsored supply of medical
Source of Cannabis Hm Contamination marijuana. According to Raber, Elzinger and Kepler [13] many of
The activity of wild weeds growing in metal-contaminated soil California’s medical cannabis patients are susceptible to the toxic
has shown hyper-accumulation of HMs and hence proving their effects of these elements due to their compromised immune systems or
phytoremediation mettle [37]. A number of studies have now been hepatic illnesses. This is tantamount to state-sponsored medical fraud.
carried out on marijuana that provides convincing evidence that
Another HM, cadmium (Cd) is also known to be one of the
the weed is an active accumulator for HMs such as lead, cadmium,
most phytotoxic of the soil-based HMs [24,51]. Marijuana is one of
magnesium, copper, chromium, and cobalt. The sources of these
the best phytoextractors for Cd [49]. Except for roots, the highest
HMs are the result of human (anthrogenic) activities such as mining,
concentrations of Cd are found in the marijuana leaves, whereas the
smelting, sewage sludge and automobile emissions [38-45].
lowest are typically observed in seeds [52]. Marijuana has been found
The U.S. Department of Interior, Geological Survey has reported to be highly cadmium-tolerant and very useful in bioaccumulation of
that most of the mercury used in gold recovery in California was cadmium with its superior ability to accumulate cadmium in the smoke-
obtained from mercury deposits on the west side of California’s able harvest. Marijuana does have a high capacity for phytostabilization
Central Valley. Total mercury production in California between 1850 and is tolerant to contaminants. The importance to public health risk
and 1981 was more than 220,000,000 pounds (https://pubs.usgs.gov/ is marijuana’s ability to accumulate metals along with stabilization of
fs/2005/3014/). The government reports that most of this mercury contaminated areas like the “Emerald Triangle” and, unlike most plants
was exported around the Pacific Rim or transported to Nevada and used in bioremediation, it offers additional end uses. The extraction
other western states (i.e., Colorado, New Mexico). In relations to HM capability for heavy metals from the soil makes marijuana an ideal
residues in soil 12% (26,000,000 lb) of the mercury mined in California soil phytoremediation agent. The property of marijuana to scavenge
was used for gold recovery in California, lending to its relative high cadmium from contaminated soils of northern California, Oregon
contribution to the total eco-burden of soil-based HMs [46]. and Washington should focus the attention of public health regulators
Three western states in the US lead the country in the agricultural to the potential negative effects that could be caused due to potential
growth, processing, and sales of marijuana for recreational and metal accumulation on the health of patients for whom the “medical
therapeutic use: California, Oregon, and Washington. Among the marijuana” is grown.
world’s largest producers of illicit opium, the United Nations Office
of Drug Control (UNODC) and other law enforcement agencies Cd concentrations of up to 72 mg/kg (soil) have been reported to
commonly refer to areas of the mid-East (Iran, Pakistan, and have no negative effect on germination of marijuana, and exposures of
Afghanistan) and Asia (Burma, Thailand, Viet Nam and Laos) as the up to 100 ppm, has no significant effects on the morphological growth
“Golden Crescent” and “Golden Triangle”, respectively. Based on the of the marijuana plant. The highest concentration of cadmium tolerance
astronomical MGOs located in Mendocino, Humboldt, and Trinity has been shown in the roots of marijuana at a maximum 830 mg/kg
Counties of northern California this hot bed of licit and illicit marijuana without affecting the growth of the plant [53]. Plants generally do not
plots is now referred to as the “Emerald Triangle”. accumulate elements beyond near-term metabolic needs, which are

Pharmaceut Reg Affairs, an open access journal Volume 7 • Issue 1 • 1000202


ISSN: 2167-7689
Citation: Gauvin DV, Zimmermann ZJ, Yoder J, Tapp R (2018) Marijuana Toxicity: Heavy Metal Exposure Through State-Sponsored Access to “la
Fee Verte”. Pharmaceut Reg Affairs 7: 202. doi: 10.4172/2167-7689.1000202

Page 5 of 10

small ranging from 10 to 15 ppm of most trace elements [54]. Hyper- may not contribute to a statistically significant increase in total body
accumulators like marijuana are exceptions to the rule and have been burden for each metal, the risk assessment required for FDA approval
reported to accumulate toxic metals much beyond the trace-element must also focus on more local changes to cellular environments of
limits up to the levels of thousands of ppm. During the phytomediation the mouth, throat, and lung with respect to direct cytotoxic insults
process soil contamination is transported from roots to shoots, which and the astronomical duration of tissue exposures long after the
are harvested, causing contamination to be removed while leaving the “buzz” of intoxication. In regard to CDC risk assessments, the lifetime
original soil undisturbed [54]. cancer mortality risk coefficients have been calculated for nearly all
The high concentrations of HM accumulation achieved in radionuclides, including cadmium. The coefficients for inhalation are
marijuana cannot be explained exclusively by passive ion uptake. The greater than for ingestion. For marijuana and tobacco, the toxicity
hyper-accumulatory properties of marijuana are dependent upon value for estimating the risk of cancer from inhalation exposure
several factors. Polychelatin formation is one of the important basic is called a Unit Risk (UR), which is an estimate of the chance that a
factors for the scavenging of HMs, especially in the context of Cd person will get cancer from continuous exposure to a chemical in air
tolerance [55]. Technically, polyamines strengthen the defense response at a concentration of 1 milligram per cubic meter (mg/m3). The UR for
of plants and modulate their activity against diverse environmental cancer risk for inhaled cadmium from smoked marijuana is 1.8 mg/m3.
stressors including metal toxicity [56], and oxidative stress [57]. The The inhalation of HMs may or may not support a role of smoked
other class of significantly notable chelating compounds in marijuana marijuana as a cancer risk [61], but toxic metals may also contribute
is metallothioneins as shown in Table 1. to non-cancer health risks such as cardiovascular diseases [62-64], and
Malik et al. [58] has reported that marijuana has a high translocation other maladies such as Chronic Obstructive Pulmonary Disease (COPD)
rate for another HM, zinc, with an estimated translocation factor and smoking related interstitial lung disease that are characterized by
value of>1.0. This translocation factor promotes the accumulation of sensitization, chronic inflammation, or tissue remodeling [65-68].
Zn into the smokable parts of marijuana comparable to other HMs. Wang et al., [6] has clearly demonstrated that even 1 minute exposure
Malik et al. [58] report that accumulation of zinc is maximal in shoots to second hand marijuana smoke substantially impairs endothelial
and it shows marijuana’s full hyper-accumulating property by storing function in rats for at least 90 minutes. These effects were greater than
the HMs in their shoots (compare root concentrations relative to comparable exposure to tobacco second hand smoke and did not rely
shoot concentrations of zinc). Juknat et al. [59] has reported that the on the presence of cannabinoids in the main stream smoke.
non-psychoactive element of smoked marijuana, cannabidiol (CBD) Repetitive inhalations of unfiltered marijuana smoke directly
upregulates the expression of the mRNAs for metallothionein 2 (Mt2), expose the oral and pulmonary epithelium to relatively high
N-myc-downstream regulated gene 1 and matrix metalloproteinase concentrations of marijuana-based condensates plus HMs. Small
23 in vivo. CBD upregulates the zinc transporters: ZnT1/Slc30a1 and particles and soluble toxic substances can be directly absorbed into
Zip4/Slc39a4. Interestingly, Juknat et al. [59] report that CBD also epithelial and interstitial tissues prior to being passed into the general
downregulates the expression of the mRNA for the zinc transporter circulation. So, while systemic (blood, plasma, or urine) concentrations
Zip10/Slc39a10 as well as for the zinc finger protein 472. These genes, may not reflect statistically significant changes in total body burden
ZnT1, Mt2 and the zinc transporters ZIPs are known to function to these HMs selective local cells can go through changes resulting
together to control the intracellular zinc concentrations in vivo. in pathological cytotoxicities [69]. For example, smoke cadmium is a
Bernhoft [60] has described the metabolic pathway for cadmium Group 1 human carcinogen and is cytotoxic. Marijuana is one of the
after absorption. Cd is transported bound to a sulfhydryl group- best phytoextractors of soil-based cadmium and is one of the highest
containing protein like metallothionein. One-third of the inhaled concentrations of HMs in the dry material. When smoked it induces
Cd goes to liver, one-third goes to kidneys, and the residual 40% is proinflammatory cytokines as a carcinogen, and is a substance that
distributed in other tissues of the body. Critically important to the causes disease in many body tissues including lungs, liver and kidneys.
discussion of neurotoxicity of cadmium is the realization that any Pyrolysis of Hms in The Preferred Method of Dose
absorbed cadmium is excreted primarily in the urine, but because daily
excretion is only about 0.01% of the total body burden, the biological Administration
half-life is about 25 years. For the cadmium that does enter the blood Smoking marijuana and inhalation of second-hand smoke
stream, the half-life has been estimated at 75 to 128 days, but this half- are associated with inflammation, cellular atypia, and molecular
life primarily represents deposition in organs, not clearance from the dysregulation of the tracheobronchial epithelium. While marijuana
body. Consequently, blood, hair, and urine Cd levels are poor surrogates smoke shares many components in common with tobacco, it also
for body burden and chiefly reflect recent exposure, as is also true with contains a high concentration of Δ9-Tetrahydrocannabinol (THC)
the other HMs. While the presence of the HMs in marijuana may or and CBD. The inhaled cannabinoids have been shown to induce a
time- and concentration-dependent decrease in cell viability, ATP
Concentration level, and mitochondrial membrane potentials [70]. Sarafian et
Heavy metal Roots Shoots al. [70] reported acute changes (24 h) in the expression of mRNA
mg/kg Dried weight mg/kg Dried weight for caspase-8, catalase, Bax, early growth response-1, cytochrome
Lead 29 30 P4501A1 (CYP1A1), metallothionein 1A, PLAB, and heat shock factor
Copper 29 18.2 1 (HSF1) – all biomarkers for apoptosis (programmed cell death). The
Zinc 27 43.9 presence of zinc, cobalt, and cadmium, and their own direct effects on
Nickel 13.6 11.3 antioxidant and anti-inflammatory processes may interact with these
Cadmium 24.7 14.8 cannabinoid-related direct cytoxic effects. As stated above, 1/3 of these
Chromium 29.7 14.5 HMs accumulate in the kidney, often times 30 to 60-fold greater than
in the lungs [71, 72].
Table 1: Heavy metal accumulation in marijuana expressed in mg/kg of dry material.

Pharmaceut Reg Affairs, an open access journal Volume 7 • Issue 1 • 1000202


ISSN: 2167-7689
Citation: Gauvin DV, Zimmermann ZJ, Yoder J, Tapp R (2018) Marijuana Toxicity: Heavy Metal Exposure Through State-Sponsored Access to “la
Fee Verte”. Pharmaceut Reg Affairs 7: 202. doi: 10.4172/2167-7689.1000202

Page 6 of 10

Most of the consumers of recreational and medical cannabis use can accumulate in the glomerular layer of the olfactory bulbs (CNS
it or prefer it by the inhalation/smoking route. Smoke chemistry has penetration). These data further suggest that movement of the HMs
been predominantly investigated in tobacco products but a 10-year along the olfactory axons to their terminal parts in the glomeruli are
old report by Moir et al. [73] highlighted the qualitatively similar not the result of vascular uptake from the mucosa. Radioactive labeling
carcinogenic chemicals contained within both tobacco and marijuana of mercury was also discernable in the external plexiform layer of the
smoke [74-76]. Using two methods, the International Organization CNS, indicating that HMs also leave the terminal arborizations of the
for Standardization’s method, ISO 3308, and their own Health Canada axons in the glomeruli. Tjälve et al. [81] have shown similar active
method tobacco and marijuana cigarettes were analysed. The HMs transport of the HM, manganese, in rats by an initial uptake of the
contained in both smoked product included: mercury, cadmium, lead, metal in the olfactory bulbs. The HM was then seen to migrate via
chromium, nickel, arsenic, and selenium. Interestingly, marijuana secondary and tertiary olfactory pathways and via further connections
smoke contained significantly more hydrogen cyanide, aromatic into most parts of the brain and also to the spinal cord. On the other
amines, ammonia, NO (nitric oxide, nitric monoxide) and NOx (a hand, cadmium instillation into the nasal mucosa resulted in uptake of
generic term for the nitrogen oxides, [ for example, NO2] which are the metal into the anterior parts of the olfactory bulbs but not into other
major contributors to air pollution. NO, NOx, cyanide and aromatic areas of the brain. Manganese is a neurotoxic metal which in man can
amines were 3 to 5 times greater in marijuana smoke compared induce an extrapyramidal motor system dysfunction. Tjälve et al. [81]
to tobacco and ammonia concentrations were 20 times higher proposed that the neurotoxicity of inhaled manganese is related to an
than tobacco. Quantitatively, there were significantly lower HMs uptake of the metal directly into the brain via the olfactory pathways. In
concentrations in marijuana smoke condensates, however, this was due this way manganese can circumvent the systemic vasculature and the
to the marijuana supply used by Moir et al. [73] in their study. impermeable blood-brain barrier and gain direct access to the central
nervous system.
Unlike the tobacco supply the bulk marijuana used in the Moir et
al., [73] study was purchased from a Canadian hydroponic research Similar transneuronal active transportation pathways have
laboratory. With no soil-based HMs to be extracted during the been shown for another HM found in marijuana smoke, cobalt,
growth cycle of the marijuana, it was the liquid fertilizers used in the by Persson, Henriksson, and Tjälve [82]. Local instillation of nasal
hydroponic systems that were attributed as the cause of the differential cobalt accumulated in the olfactory nerve layer and the terminals of
ammonia, NO, NOx and aromatic amines reported in their study. the primary olfactory neurons in the glomerular layer of the bulb. In
Normal soil grown tobacco was compared to soil-less marijuana in this addition, cobalt migration into the interior of the bulbs was followed by
study. The soil-less growth medium of the marijuana supply required deposits into the anterior parts of the olfactory cortex, indicating that
water-soluble hydroponic vegetable fertilizers which contain nitrogen these HMs may be able to leave the terminals of the primary olfactory
in the form of nitrate and ammoniacal nitrogen. While Moir et al. [73] neurons. Memory deficits have been observed among human workers
confirmed the presences of similar HMs in tobacco and marijuana the exposed to cobalt via inhalation, and it must be considered that cobalt
study does not provide reliable data on the quantitative concentration in mainstream marijuana smoke may be neurotoxic, as well. Public
of HMs of their comparisons in this study. health risk assessments must include the proposal that inhaled HMs (as
entourage chemicals of smoked medical marijuana) is deposited in the
As discussed above, aside from cadmium, exposure to inhaled oral, nasal and pulmonary passages and that released HMs, after uptake
smoke from the unfiltered marijuana cigarette also includes arsensic, into the brain via nonvascular pathways, may cause the neurotoxicity
aluminum, chromium, copper, lead, mercury. The oral, nasal and associated with the attention, learning, and memory deficits in human
pulmonary epithelium, being the first “wet tissues” to come into marijuana users.
direct contact with airborne compounds of marijuana smoke serve
as the “ground zero” for toxic insult [77]. A non-sensory function of Results and Discussion
the olfactory and gustatory systems is the active transport by these
primary sensory neurons that may represent a mechanism of entry
Hms Oxidative stress and toxicity
into the central nervous system for compounds that are normally The systemic and cellular toxicity of metals varies with the electrical
excluded by the blood-brain barrier. Sunderman [78] has shown that charge of the cation and the local concentrations that comes in contact
aluminum, cadmium, cobalt, lead, manganese, nickel and zinc can with the cell membranes. These represent “local cellular events” that
pass via olfactory receptor neurons from the nasal lumen through occur prior to the metals entering the blood stream. For example,
the cribriform plate to the olfactory bulb. Some of these HMs (eg, Pb (lead) causes inhibition of specific enzymes involved in heme
Mn, Ni, Zn) can cross synapses in the olfactory bulb and migrate via biosynthesis and causes replacement of iron in the heme by zinc which,
secondary olfactory neurons to distant nuclei of the brain. According in turn, generates a nonfunctional zinc protporphyrine [83]. In some
to Sunderman [78], transport of the HMs via olfactory axons can occur instances, functional living cells respond to high concentrations of
rapidly, within hours or a few days (eg, Mn), or slowly over days or HMs, such as cadmium, zinc and copper, by synthesizing a family of
weeks (eg, Ni). The olfactory bulb tends to accumulate certain metals proteins call metallothioneins in an attempt to sequester the cations
(eg, Al, Bi, Cu, Mn, Zn) with greater avidity than other regions of the [84]. As stated above, excess zinc is cytotoxic. Zinc, copper, cadmium,
brain [79]. and lead form mercaptides. The presence of mercaptides rapidly induce
the synthesis of metalothionein by local cells, in an attempt to chelate
Henriksson and Tjälve [80] has shown that intranasal instillation them and avert any direct cell death from the surfeit of these oxidizing
of mercury into the right nostrils of rats resulted in much higher metals. These HMs then compete for functional iron (ferritin) that
levels of the metal in the right olfactory bulbs than in the left ones. interfere with the normal iron storage and mobilization needed
At the side of the application of mercury there was also a labeling of for healthy cell systems. Ferritin transcriptional and translational
the olfactory nerve bundles projecting to the olfactory bulbs as well as regulation is also involved with cellular interactions with cadmium,
in the olfactory nerve-fibers constituting the olfactory nerve layer of manganese, arsenic and aluminum [85-90]. Price and Joshi and Joshi et
the bulbs, which was not seen on the opposite side. These results show al. [91,92] suggested that it is ferritin that is the primary detoxification
that the local application of HMs in smoked condensate, like mercury, response to HMs.

Pharmaceut Reg Affairs, an open access journal Volume 7 • Issue 1 • 1000202


ISSN: 2167-7689
Citation: Gauvin DV, Zimmermann ZJ, Yoder J, Tapp R (2018) Marijuana Toxicity: Heavy Metal Exposure Through State-Sponsored Access to “la
Fee Verte”. Pharmaceut Reg Affairs 7: 202. doi: 10.4172/2167-7689.1000202

Page 7 of 10

It is the pivotal role of cellular iron (heme) in dealing with all of activation in the superior temporal gyri and middle temporal gyri,
these HMs administered with each inhalation (“toke”) of the marijuana insula, and supramarginal gyri and the right inferior frontal gyri as
smoke. The characteristic post-inspiratory pause (breath hold) that is well as the left cerebellum. During visual information processing tasks,
not present in tobacco smokers also sets the stage for HM exposure that THC reduced activation in the extrastriate visual cortex, and increased
initiates cytotoxicity through free radical production and cell death. activation in the lingual and middle occipital gyri corresponding
But, what about the toxic effects of HMs that do not utilize the vascular to the primary visual cortex in the left hemisphere. These areas of
system for transport into the CNS? the brain are critically linked to learning and memory functions.
O’Leary et al. [102-105] used PET scans to demonstrate reduced blood
According to Bernhoft [60], cadmium causes oxidative stress flow in these temporal, occipital and frontal cortices, as well as the
and histologically visible membrane disturbances in the central cerebellum. Hippocampal, Wernicke’s and Broca’s areas are located in
nervous system. The presence of cadmium has also been linked to these general areas of the human brain and implicate a role of THC
reductions in acetylcholinesterase activity, increase in oxidative stress in affecting these language centers, as well. These regional blood flow
markers, depletion of glutathione, superoxide dismutase 2, and other changes and decreased activity certainly correlate with the loss of high
antioxidants, as well as depletions of anti-oxidant concentration of gamma powerbands recorded from surface-based EEG electrodes.
catalase, glutathione peroxidase, and glutathione-S-transferase [93]. The question now arises as to the full impact of HMs delivered to
These changes have apparently led to apoptosis of cortical cells in the these same areas with THC from smoked medical marijuana grown
central nervous system, possibly due to phosphorylation of calcium/ in the Emerald Triangle. While previous data showed a direct neural
calmodulin dependent protein kinase II [94]. Cd can also inhibit influx basis for THC-induced changes in these CNS areas – those studies
through calcium channels [95]. that administered THC were devoid of soil-based HMs. The presence
Signs of neurotoxicity associated with marijuana use of oxidative stress-induced apoptosis associated with the transport
of HMs to these centers of learning and memory have the potential
The risk assessment plan for any drug application submitted for pose a stronger threat to the health of the patients to whom they are
license approval must be based on contemporary, scientifically valid, medically prescribed. Humans with elevated blood or urine cadmium
reliable and legally defensible data. In any federally mandated health concentrations demonstrate decreased measures of attention and
safety assessment review on marijuana conducted by the CDC, FDA, memory impairments [106], as well as a significant decrease in low-
NIDA or DEA the data from low potency marijuana of the 1960s to frequency hearing thresholds [107]. In nonclinical toxicity studies, rats
2000 have minimal relevance with respect to the current true yield of with high urinary cadmium also exhibit decreased learning ability. The
THC and CBD concentrations on today’s market. Marijuana samples significant threat to human health from inhaled marijuana smoke that
are generally found to contain>12% THC and solvent extracted hash contains Cd, Co, Ni, Zn is further demonstrated by the findings that
oils (butane-hash oils) have been found to contain up to 90% THC (cf) intranasal cadmium exposures destroys olfactory nerve function in the
[96]. Aside from these relatively astronomical cannabinoid content rat (direct neuro/cytotoxicity: Czarnecky et al., [108]. Cadmium also
characteristics, risk assessments cannot diminish or deny the basic raises the frequency of spontaneous cortical electrical activity in the
characteristics of the marijuana plant as a phyto-extractor of soil- rodent and lengthens the latency of sensory-evoked potentials. These
based HMs. Therefore, FDA must take into account the entourage of impairments are without detectable Cd brain deposits [93]. Given
other toxic chemicals, like HMS, that are delivered in the palliative the ubiquity of Cd in the current large-growth environments of the
smoked product harvested from current geographical locations of the west coast states that grow a preponderance of all medical marijuana
agribusiness source of supplies to state-sponsored dispensaries, i.e., the prescribed in the US, public health policy makers must take account
“Emerald Triangle” [96]. of the comorbidity of Cd exposures to the recent cultivation of high
potency THC- and CBD-based medicines and the other harmful
“Clean” marijuana is not benign to CNS injury. In 2014, Skosnik
chemicals found in the hybridized weeds of 2018.
et al. [97] reported finding a significant reduction in EEG “high power
gamma wavebands” in cannabis users who smoked marijuana at least We are at the brink of a public health crisis with state-sponsored
once per week over the last four weeks with no other drug use over poisoning of clinical patients prescribed medical cannabis by health
the past 3 months. EEG gamma wavebands (30 to 80 Hz) are believed care professionals. Primum non nocere – first do no harm! And Caveat
to play a key role in sensory data registration and the integration and emptor–buyer beware! There are no safety guarantees to the patients
binding of perceptual features of the environment that represent basic who assume a safe pharmaceutical grade product is being prescribed
associative learning processes and a measure of conscious awareness. by their health care professional and they certainly are not guaranteed
These data were similar to previous studies of marijuana smokers that safe and effective plant product from the state-sponsored dispensary
utilized evoked and steady-state EEGs [98-100]. These changes in that fills that prescription for the unwitting ill patient. The state-
relative power of high frequency wavebands in the EEGs represent a sponsored supply of marijuana in California, Colorado, Washington
neural correlate for various higher perceptual and cognitive processes and Oregon for medical or recreational use has a high probability of
involved in learning and memory and are consistent with the current being contaminated with toxic HMs through the basic botanical and
view that cannabinoids play a general role in the generation and genetically-based phytoremediation features of their “wonder plant”.
maintenance of neural synchrony in temporal lobe functions related to Contemporary public health risk assessments for medical and
learning and memory functions. recreational marijuana must take into account:
In 2011, Winton-Brown and colleagues [101] reported that THC 1) the current high potency THC containing product now on store
(oral administered capsules) increased self-reported states of anxiety, shelves of the state-sponsored dispensaries,
intoxication, and positive psychotic symptoms. Additionally, these
authors reported bilateral decreases in activation of temporal cortices 2) the neurotoxic exposures from rodenticides, insecticides,
during auditory processing as well as decreases in activation of visual miticides, fungicides, synergists and growth regulators being used
cortices during processing of visual information using fMRI. During in the current federally-unregulated agricultural production and
basic information processing of auditory signals, THC reduced harvesting of the botanical, and

Pharmaceut Reg Affairs, an open access journal Volume 7 • Issue 1 • 1000202


ISSN: 2167-7689
Citation: Gauvin DV, Zimmermann ZJ, Yoder J, Tapp R (2018) Marijuana Toxicity: Heavy Metal Exposure Through State-Sponsored Access to “la
Fee Verte”. Pharmaceut Reg Affairs 7: 202. doi: 10.4172/2167-7689.1000202

Page 8 of 10

3) the entourage environmental HM contaminants that result from and bind-the-hands of federal agencies involvement in state initiatives
the basic chemo-attractive affinity of the marijuana plant itself. that intentionally violated and superseded federal and international
laws regarding schedule control status of marijuana [109].
The legend that the emperor “Nero played the fiddle while Rome
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ISSN: 2167-7689
Citation: Gauvin DV, Zimmermann ZJ, Yoder J, Tapp R (2018) Marijuana Toxicity: Heavy Metal Exposure Through State-Sponsored Access to “la
Fee Verte”. Pharmaceut Reg Affairs 7: 202. doi: 10.4172/2167-7689.1000202

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Citation: Gauvin DV, Zimmermann ZJ, Yoder J, Tapp R (2018) Marijuana Toxicity: Heavy Metal Exposure Through State-Sponsored Access to “la
Fee Verte”. Pharmaceut Reg Affairs 7: 202. doi: 10.4172/2167-7689.1000202

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